Smooth Muscle Apoptosis During Vascular Regression in Spontaneously Hypertensive Rats

Abstract

We previously reported that apoptosis is increased m smooth muscle cells cultured from the aorta of spontaneously hypertensive rats versus normotenslve controls. As an mtttal m viva exploration, we now exammed smooth muscle cell apoptosis regulation during the regression of vascular hypertrophy m the thoracic aorta media of spontaneously hypertensive rats receiving the antihypertensive drug enalapnl (30 mg kg-' d-'), losartan (30 mg kg-' d-'), mfedipme (35 mg kg-' d-l), hydralazme (40 mg kg-' d-'), propranolol(50 mg kg-' d-'), or hydrochlorothiazide (75 mg kg-' d-') for 1 to 4 weeks starting at 10 to 11 weeks of age Three criteria were used to evaluate smooth muscle cell apoptosis (1) ohgonucleosomal fragmentation of the extracted aortm DNA, (2) reduction in aortic DNA content, and (3) depletion of smooth muscle cells m the arterial media Arterial DNA synthesis was evaluated by [3H]thymidme mcorporation m viva After 4 weeks of treatment, systohc blood pressure was reduced stgmficantly by >42% wtth losartan, enalapnl, and hydralazme, and by 23% with mfedipme, versus control values of 22025 mm Hg. However, these agents affected vascular growth and apoptosis differently Losartan, enalapnl, and mfedipme stimulated smooth muscle cell apoptosrs threefold to fivefold before there was a significant reduction m DNA synthesis (>25%), vascular mass (>19%), or vascular DNA content (>38%), and these treatments markedly reduced (by 38% to 50%) medial cell number as measured at 4 weeks by the three-dimensional disector method Losartan and mfedipme stimulated smooth muscle cell apoptosis before reducing blood pressure In contrast, hydralazme did not affect vascular mass, apoptosis, or DNA synthesis, although blood pressure was lowered Propranolol or hydrochlorothiazlde failed to affect hypertension or vascular growth Thus, smooth muscle cell apoptosls represents a novel therapeutic target for the control of hypertensive vessel remodeling m response to therapeutic agents (Hypertension. 1997;29[part 2]:340-349.) Key Words l apoptosts l smooth muscle cell . angtotensm II l calcmm channel antagonist S tudies m humans and in experimental models of hypertension have clearly demonstrated the importance of vascular structure m the regulation of blood pressure i-6 Increased vascular mass is an important feature of hypertensive vessels. At the level of small muscular arteries, vascular hypertrophy accompanied by smooth muscle cell (SMC) hypertrophy or hyperplasia acts as an amplifier for elevated vascular resistance and blood pressure.7%8 At the level of the aorta and its main branches, increased mass and ngidtty of the arterial wall contribute to systolic hypertension and represent an mdependent risk factor for left ventricular hypertrophy.9 The remodeling of vascular structure, mcludmg the regression of vascular hypertrophy, is now considered a key therapeutic target in the effort to reduce mortahty and morbidity associated with high blood pressure lo-13Increased vascular mass associated with the replication and accumulatio...

Time Course of Vascular Structural Changes During and After Short-Term Antihypertensive Treatment

“…Previous evidence supporting an early remodeling process has shown in aorta that there is a "burst" of vascular smooth muscle cell apoptosis within the first 2 weeks of antihypertensive treatment. 30,31 Regardless of the precise mechanism of remodeling, the present findings describe a time course of vascular structural changes that occur during both the on-and the off-treatment time periods. Specifically, changes in the index of lumen dimensions were not fully consolidated until 2 to 3 weeks after stopping treatment.…”

Vascular Apoptosis and Involution in Gliomas Precede Neovascularization: A Novel Concept for Glioma Growth and Angiogenesis

“…Smooth muscle and endothelial cell apoptosis have been shown to play an important role in vascular regression in physiological and pathological processes (Bennet and Boyle, 1998;deBlois et al, 1997;Goede et al, 1998;Honma and Hamasaki, 1998;Modlich et al, 1996;Shabisgh et al, 1999;Walker and Gobe, 1987;Walker et al, 1989). For example, there is increasing evidence showing that vascular smooth muscle cell apoptosis is involved in the pathogenesis of atherosclerosis and restenosis following angioplasty (Bennet and Boyle, 1998).…”

Short-term ACE inhibition confers long-term protection against target organ damage

“…Certain antihypertensive drugs have been shown to provide long-term benefits beyond blood pressure lowering. For example, angiotensin converting enzyme (ACE) inhibitors have been shown clinically 2 and experimentally, 3,4 to reduce cardiovascular mortality, in part by decreasing cardiac and vascular hypertrophy 5 as well as cardiac and renal fibrosis. [6][7][8] We have previously demonstrated in experimental models of hypertension that ACE inhibitor-induced regression of cardiac hypertrophy is mediated in part by apoptosis of fibroblasts in addition to reduction in cardiomyocyte size in the left ventricle (LV).…”